Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
National Institutes of Health (NIH)
National Center for Complementary and Integrative Health (NCCIH)
Reissue of PAR-18-696 - Clinical Coordinating Center for NCCIH Multi-Site Investigator-Initiated Clinical Trials of Natural Products (Collaborative UG3/UH3 Clinical Trial Required)
September 28, 2023 - Notice of Intent to Publish a Notice of Funding Opportunity for Clinical Coordinating Center for NCCIH Multi-Site Investigator-Initiated Clinical Trials of Natural Products (Collaborative UG3/UH3 Clinical Trial Required). See Notice NOT-AT-24-021
March 28, 2023 - Notice to Extend NCCIH's PAR-20-218, PAR-20-217, PAR-20-216, PAR-20-215, and PAR-20-219. See Notice NOT-AT-24-003.
NOT-OD-23-012 Reminder: FORMS-H Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2023 - New Grant Application Instructions Now Available
NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022
October 28, 2021 - Reminder: FORMS-G Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2022 - New Grant Application Instructions Now Available. See Notice NOT-OD-22-018.
September 13, 2021 - Updates to the Non-Discrimination Legal Requirements for NIH Recipients. See Notice NOT-OD-21-181.
August 5, 2021 - New NIH "FORMS-G" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2022. See Notice NOT-OD-21-169.
August 5, 2021 - Update: Notification of Upcoming Change in Federal-wide Unique Entity Identifier Requirements. See Notice NOT-OD-21-170
April 20, 2021 - Expanding Requirement for eRA Commons IDs to All Senior/Key Personnel. See Notice NOT-OD-21-109
PAR-20-216 - NCCIH Natural Product Mid Phase Clinical Trial Cooperative Agreement (U01 Clinical Trial Required)
PAR-20-217 - NCCIH Natural Product Early Phase Clinical Trial Award (R33 Clinical Trial Required)
PAR-20-218 - NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required)
PAR-20-219 - Natural Product, Multi-Site, Clinical Trial, Data Coordinating Center (Collaborative U24 - Clinical Trial Required)
93.213
This Funding Opportunity Announcement (FOA) encourages cooperative agreement applications for investigator-initiated, multi-site, clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. Applicants should describe plans for a Clinical Coordinating Center to develop and implement the proposed multi-site clinical trial. The objective of the Clinical Coordinating Center is to provide the design scientific rationale and a comprehensive scientific and operational plan for the clinical trial. The Clinical Coordinating Center is expected to be responsible for project management, participant recruitment and retention strategies, performance milestones, scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven, cooperative agreement (UG3/UH3) funding mechanism.
In addition, an accompanying Data Coordinating Center application, submitted under PAR-20-219, proposing a data analysis and data management plan for the clinical project is required.
Both a Clinical Coordinating Center application and a corresponding Data Coordinating Center (DCC) application need to be submitted simultaneously for consideration by NCCIH.
30 days prior to the application due date
New Applications: July 20, 2020; February 01, 2021; October 01, 2021; June 01, 2022; February 01, 2023; June 05, 2023/p>
Revision, Resubmission Applications: July 20, 2020; February 17, 2021; October 15, 2021; June 15, 2022; February 15, 2023; June 15, 2023
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
September 07, 2020; May 07, 2021; January 07, 2022; September 07, 2022; May 07, 2023; September 07, 2023
All applications are due by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
November 2020, July 2021, March 2022, November 2022, July 2023, November 2023
January 2021, October 2021, May 2022, January 2023, October 2023, January 2024
April 2021, December 2021, July 2022, April 2023, December 2023, April 2024
Not Applicable
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
Background
The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products (i.e. botanicals, probiotics, and products marketed as dietary supplements) for which there is compelling preclinical or preliminary clinical evidence for potential health benefit. NCCIH is particularly committed to identifying effective complementary health approaches for management of symptomatic conditions that are commonly treated in primary care such as sleep disturbance, pain, or mild mental health conditions (e.g., depression, anxiety disorders, and post-traumatic stress). This includes examining the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system. It also includes studies exploring the effects of cannabinoids and terpenes in early phase clinical trials for the management of the symptomatic conditions noted above.
Clinical trials of natural products are maximally informative if they incorporate well-formulated biological hypotheses, are built on a sound foundation of basic mechanistic and pharmacologic understanding, and incorporate assessment of defined replicable biological effects. Biological signatures of the natural products may be biologically based mechanisms or behavioral processes such as an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes. In some cases, a fundamental understanding of given natural product’s biological target, or mechanism of action has been clearly established (e.g. compound’s affinity for a specific receptor is well established). It is also recognized that for certain conditions (e.g., pain), a direct biological effect or biological signature may not be possible or practical with human participants.
When a mechanism of action has already clearly been established or when measuring a biological signature is not possible, investigators should contact a Program Director at NCCIH to discuss what funding mechanism is appropriate. In all cases, data demonstrating bioavailability of the natural product is required before conducting efficacy trials, when absorption of the natural product is required for activity. A careful translational research process is as important for trials of natural products as it is for the study of conventional pharmaceuticals. Critical to this process is the development of measures of a biological or behavioral effect and refinement of appropriate outcome measures for a clinical condition.
A clinical trial is defined by NIH as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Investigators considering applying to the NCCIH for a clinical trial award should refer to the NCCIH Clinical Trials Policy web site. Information about NCCIH Policies, Guidelines and Sample Templates for Clinical Trials at: https://www.nccih.nih.gov/grants/toolbox.
Overview of NCCIH Natural Products Clinical Trials Research Funding Opportunities
NCCIH has designed its natural products clinical trials program to support investigator-initiated studies with funding mechanisms appropriate to the stage of the translational research process. This includes pre-clinical/animal studies (which may use Parent R21 or R01 FOAs), human mechanistic studies to determine and replicate the biological effect of a given natural product (phased innovation awards using R61/R33), clinical trials to determine the optimal dose and/or determine which patient phenotypes will be responders versus non-responders, and multi-site clinical trials to perform definitive efficacy studies (UG3/UH3 with companion U24 mechanism).
The following research funding mechanisms have been established by NCCIH to assist in supporting research and development of a natural product along a translational research continuum from early exploratory pre-clinical or first in human research through multi-site efficacy trials. Depending on the extant evidence and research for a given natural product, applicants may use the appropriate FOA to support the next step in clinical trial research.
Clinical Trial Planning Phase - Determining Biological Signature (R61/R33, PAR-20-218 and R33, PAR-20-217)
To maximize the impact of a natural product clinical trial, it is highly desirable to establish an objective measure or validated psychological process measure of the impact of the natural product, hence forth known as a biological signature in the context of the study conditions. In general, a research grant application submitted under the R61/R33 (or R33) should precede submission of a multi-site efficacy trial via the UG3/UH3 and companion U24 mechanisms described below, although this is not a requirement and such data may be available or can be obtained through other means. This biological signature may be a measure of the postulated mechanism of action by which the natural product may ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be biologically based mechanisms or behavioral processes such as an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.
The R61/R33 should be used to measure the pharmacokinetics (if applicable) of the product and the impact of the natural product on a biological signature (R61 phase), replicate the impact on and determine the reproducibility of the biological signature in a separate study (R33 phase), and when possible determine the dose of the natural product that optimizes its impact on the biological signature (R33 phase). The data collection supported under the R61/R33 or R33 should be finished and the data analysis completed before the U01 or UG3/UH3 is submitted.
Natural Product Mid-Phase Clinical Trial Cooperative Agreement (U01, PAR-20-216)
The Mid-Phase Clinical Trial Award FOA is intended to complete collection of preliminary data needed to inform the design of a fully powered multi-site efficacy trial. The U01, therefore, supports research that builds upon work that has 1) determined the pharmacokinetics of the product and 2) identified and replicated a biological signature for a given natural product. Investigators should only apply for the U01 Mid-Phase Clinical Trial Cooperative Agreement if there is substantial evidence that the proposed biological signature of the natural product has been detected and replicated with research participants or patients. The U01 may also be used to investigate a well-characterized natural product for a new clinical condition if the evidence of a biological signature (i.e., mechanism of action) is known through previous research and extant data.
It is recognized that for certain conditions (e.g. pain), a direct biological effect or biological signature may not be measurable in human participants for a variety of reasons. In such instances, a strong justification is needed for why measuring the impact on a biological signature is not possible or impractical with human participants is required. In these cases, investigators should consider including other objective measures that may be a marker of the mechanism of action and provide evidence of a biological or behavioral effect of the natural product in human participants. The U01 clinical trial FOA will support natural product clinical trials (usually phase II) such as dosing and formulation optimization of the natural product when they are needed to plan for a future multi-site randomized clinical trial; or when it is necessary to determine which patient phenotypes will be likely responders versus non-responders to the natural product to inform inclusion/exclusion criteria of a future multi-site efficacy trial. Trials supported by the U01 should also collect additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, and complete collection of follow-up data.
Multi-Site Investigator-Initiated Clinical Trials Cooperative Agreement Award (UG3/UH3, PAR-20-215)
The UG3/UH3 FOA will support applications to implement a multi-site, clinical trial of a natural product (Phase III and beyond). Under this phased award, the UG3 phase supports the planning and development of resources necessary to perform the efficacy trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the efficacy clinical trial. The UG3/UH3 award is used to implement a Clinical Coordinating Center (CCC) for investigator-initiated multi-site clinical trials of natural products. In addition, multi-site clinical trials require a companion Data Coordinating Center (DCC) application (U24) be submitted with and linked to the CCC application. Both applications undergo peer review simultaneously. Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Multiple sites are necessary for efficacy trials to increase generalizability of findings and enhance recruitment efficiency as well as representativeness of the participants. Multi-site clinical trials are expected to be designed with a minimum of 90% power for the primary outcome in order to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. The Clinical Coordinating Center for Multi-Site Trials FOA runs in parallel with a companion FOA (PAR-20-219) that encourages applications for the companion DCC. Multi-site trials will be expected to achieve the required phase III trial requirements of NIH (see: https://humansubjects.nih.gov/glossary and http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm).
Purpose of the Multi Site Investigator Clinical Trials Award (UG3/UH3) (This FOA)
This FOA invites cooperative agreement applications for investigator-initiated, multi-site, clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. The Clinical Coordinating Center (CCC) will have plans to develop and implement the proposed multi-site clinical trial. Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.
This CCC FOA runs in parallel with a companion FOA (PAR-20-219) that encourages applications for a corresponding Data Coordinating Center (DCC). Both a CCC application and a corresponding DCC application need to be submitted simultaneously for consideration by NCCIH.
Investigators must contact the US Food and Drug Administration (FDA) prior to submitting an application to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research. Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://NCCIH.nih.gov/grants/toolbox) to learn more about NCCIH's requirements for clinical research and NCCIH’s policy on natural product integrity (http://NCCIH.nih.gov/research/policies/naturalproduct.htm). Clinical trials supported by this FOA will have to adhere to the NIH Policy on Good Clinical Practice Training (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html)
Preliminary Data Requirements:
This FOA is appropriate when there a clear and compelling rationale, a rigorous empirical basis, and scientific premise, which should include preliminary data from animal studies and previous human studies. The following preliminary data from human studies (preferably published in the peer-reviewed literature) on the same product and specific formulation as proposed in the current application are required:
For the purposes of this FOA, it is preferred that there be an established, measurable, reproducible, well-characterized biological signature for a given natural product in human subjects. However, NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the biological impact of a natural product. In these circumstances the study should be justified by: (1) a clear rationale for why studying a biological signature in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product; and (3) strong compelling preliminary data to warrant further study of a natural product in clinical studies. . In other cases, a fundamental understanding of a given natural product’s biologic target, or mechanism of action has been clearly established (e.g., compound’s affinity for a specific receptor is well established). In these situations, investigators are also encouraged to contact NCCIH Scientific/Research staff to determine whether the UG3/UH3 is the appropriate funding opportunity for the proposed clinical trial.
Structure
This FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). There should be clear objectives for both a UG3 and a UH3 phases.
Phases of Award
The UG3 phase will support the development of case report forms and other resources necessary to the performance of the trial; further development and finalization of study partnerships including signed contracts with performing clinical sites; single Institutional Review Board as well as Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applications that provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting feasibility of trial launch, conduct, and completion, coupled with on-time and on-budget performance milestones are strongly encouraged. All regulatory approvals should be obtained prior to the end of the UG3 award. Provision of the necessary natural products, matched placebos, or other resources should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Subject to NCCIH funding availability and scientific priorities, UH3 awards will be made after administrative review with attention to the extent to which agreed upon milestones have been met.
Milestones
Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans must be guided by milestones that will be reached at the end of the UG3 phase. Milestones are to be performance-based to achieve completion of the trial on time and on budget. UG3 projects that have met milestones will be assessed administratively to determine eligibility for transition to the UH3 implementation phase.
This FOA will support applications that include a series of milestones for completion of the clinical trial (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NCCIH will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NCCIH staff will closely monitor progress at all stages, milestones, accrual, and safety.
NCCIH Priorities for Clinical Trials of Natural Products
As NCCIH's clinical research portfolio matures, NCCIH has identified certain areas of high priority. Particular focus is on management of conditions for which natural products are widely used by the public and where there is evidence of postulated mechanisms of action. For this FOA, NCCIH considers the following two general topic areas to have high program priority:
NCCIH encourages applications to this FOA that meet the above criteria and also address health disparities, symptom management in patients with HIV/AIDS, utilize special populations such as older adults, children, underrepresented minorities, individuals in the military, or veterans.
Applications proposing research topics not identified above as high programmatic priority will be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding.
Clinical Trials Not Responsive to this FOA
The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and will not be reviewed:
Specific Areas of Research Interest
Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submitting to this FOA. Early contact (12 weeks prior to submission is encouraged) provides an opportunity for IC staff to discuss the scope and goals, and to provide information and guidance.
See Section VIII. Other Information for award authorities and regulations.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
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The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The combined budgets of the CCC and DCC will be used to determine whether the policy regarding direct costs of $500,000 or more in any year will be applied (https://nccih.nih.gov/grants/policies/over500k-clinical-trials).
The scope of the proposed project should determine the requested project award period.
The project period for the UG3 phase will be up to 1 year.
The period of award for the UH3 phase is expected to be 4 years. With strong justification, up to 6 years for the UH3 may be requested.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Governments
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
Multiple PDs/PIs are allowed on any single application. Because the FOA already supports a team approach between groups of experts across sites and collaborating applications, the designation of multiple PDs/PIs on a single application may be less likely to apply. PD(s)/PI(s) from each linked application should not be designated as multiple PDs/PIs on each application of a collaborative set.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
This FOA only accepts applications that are part of a collaborative set of multiple applications. A set must contain 2 applications, 1 UG3/UH3 application to this FOA and 1 U24 application to PAR-20-219.
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Martina Schmidt, Ph.D.
Telephone: 301-594-3456
Email: [email protected]
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing (DMS) Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
Descriptive Title of Applicant's Project:
To allow NIH to identify a group of applications as a related set of collaborative applications, the titles for each application in the set must have the following format: a 1/N indicator + Identical Title (e.g., 1/2 , where the 1/2 means this is site 1 of the clinical coordinating center of the set. The data coordinating center site will be labeled 2/2). Titles may not exceed 200 characters in length, including the tag, e.g., 1/2, at the beginning of the title.
Cover Letter Attachment:
The Cover Letter is one pdf file only. The following collaborative information is required in the cover letter: a listing of all the applications that are part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s), 2) the Title (including the tag, e.g., "1/2"), and 3) the Applicant institution. Each site should submit an identical listing. If applicable, the letter should indicate the name of the NCCIH program officer with whom the project has been discussed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Other Attachments: The attachment listed below must be completed and attached or the application will not be peer reviewed.
A Project Management Plan must be provided as an "other attachment" called "CCC Project Management Plan.pdf" and must not exceed 3 pages. The Project Management Plan should describe the evidence-based strategy that will be used throughout the project to ensure that the unique goals of the clinical trial are met. Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The project management plan should describe the planning team and identify control points and processes that are key to scientific and fiscal performance. This will include a description of the organizational strategy that defines internal control points and business roles. A description of the key methodology, standards, and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the team, in collaboration with the DCC, will proactively evaluate and prioritize issues that jeopardize study goals and lead to the development of corrective responses to resolve fiscal and logistical issues (risk planning) in a timely manner. Describe processes required for orderly project closure. In summary, the project management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time. The project management plan should include risk mitigation or contingency plans.
All instructions in the SF424 (R&R) Application Guide must be followed.
Biographical Sketches: The application for the CCC must include only the personnel and corresponding biographical sketches for the key personnel for that application. All personnel involved in the conduct of the clinical trial are Key Personnel and must provide an NIH Biosketch whether or not they are budgeted. The Program Director (PD)/ Principal Investigator (Pl) (or Multi-PDs/Pls) for the companion DCC cannot be listed as key personnel in the CCC application.
The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of clinical trials and have expertise in the content area of the trial, as well as experience conducting trials under an FDA IND. The experience of all key personnel must be carefully documented. Most clinical trials will require a multidisciplinary team (clinician, statistician, data manager, study coordinator(s), etc.) and the application should reflect their roles and responsibilities in the design and implementation of the study protocol.
R&R Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
Separate itemized budgets must be prepared for each subcontract and/or for each collaborating clinical site or core, if multiple sites or cores are proposed.
Include budget support for personnel to travel to a yearly in-person steering committee and/or other meeting of investigators and NCCIH. In addition, include budget support personnel to attend the semi-annual DSMB meeting/calls.
If parts of the costs of the trial are to be provided by sources other than NCCIH, these contributions must be presented in detail in the budget justification. Include budget support for the publication and dissemination of results
Note: Do not include budget support for the DSMB. An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH and budget support for the DSMB will be provided by NCCIH.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Other Plan(s):
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy
Note: Discuss the following without duplicating information collected in the PHS Human Subjects and Clinical Trials Information Form.
The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application should present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the approach to data collection and analysis.
The following criteria must be addressed:
Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.
Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms.
Approach: The research approach section should include a description of the supporting data (including strengths and weaknesses of the published literature), clinical trial experience, the experimental approach, and a milestone plan.
Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies that show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. Applications must include the following preliminary data from human studies of the same product and specific formulation as proposed in the current application (preferably published in the literature):
Experimental Approach: The proposed experimental approach should include an appropriate design and the rationale for the particular design chosen (e.g. explanatory, cluster-randomized, pragmatic). The experimental approach description should include:
Letters of Support
Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.
If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Section 2 - Study Population Characteristics
2.4 Inclusion of Women, Minorities, and Children
Describe strategies for outreach to minorities and women.
2.5 Recruitment and Retention Plan
Describe the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP).
Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations. Documentation of availability of eligible subjects at clinic sites, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the clinical study or trial. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) , as well as the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring). An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH. At the first meeting in the UG3 phase, the DSMB will review the awardee’s protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, its ethical responsibilities, to the participants as well as to the integrity of the study, are of paramount importance to the NCCIH. The DSMB will meet in person or by phone at least twice a year. Applicants should not propose DSMB members in the application, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer reviewer committee that will evaluate the applications for scientific merit. For renewal applications, applicants should provide a list of the DSMB members in the application.
3.5 Overall Structure of the Study Team
The Overall Structure of the Study Team attachment should describe the study organization and administration, and include a communication plan. The attachment can include, but is not necessarily limited to: a description of committee structures needed to manage the complexity of the trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any sub-contractors or providers of services, personnel, or facilities. The plan should explain how these will integrate with the organizational framework described in the collaborating DCC application and should address how the CCC and DCC will coordinate leadership for clinical trial implementation. The communication plan should include a description of the coordination between the separate components including NCCIH and identify the key channels used to reach and inform each stakeholder group and receive feedback. The organization plan should also describe how disputes will be resolved between the CCC, DCC and all stakeholders.
Section 4 - Protocol Synopsis
4.6. Will the study use an FDA-Regulated intervention?
The proposed clinical trial must use a natural product (such as botanical, herbal, dietary supplement, probiotic, vitamin or mineral) for this FOA. The attachment in this section should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct the trial; and associated timeline to complete these approvals. For trials using an FDA regulated product that require an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-US regulatory agency the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed R61 or R33 trials, the IND must be submitted to the FDA with no clinical-hold imposed by the FDA prior to application being funded.
4.7 Dissemination Plan
Describe how the CCC will facilitate and support timely publication and dissemination of results as appropriate and consistent with achieving the goals of the program.
Section 5 - Other Clinical Trial-related Attachments
5.1 Other Clinical Trial-related Attachments
The following attachments must be included as a part of the cooperative agreement application. Attachments permit expansion of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.
1. Clinical Trial Experience
Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in trial coordination in the last 5 years. One table must be provided for each study record with a unique filename for each study record as an attachment (e.g. "Clinical Trial Experience1.pdf" , "Clinical Trial Experience 2.pdf", etc) and must not exceed 3 pages.
The table columns should include:
Column A: clinical trial title
Column B: applicant's role in the trial
Column C: a brief description of the trial design
Column D: planned enrollment
Column E: actual enrollment
Column F: number of sites
Column G: whether the trial(s) were completed on schedule or not
Column H: publication reference(s)
2. Milestone Plan
One Milestone Plan must be provided for each study record with a uniqe filename for each study record(e.g. "CCC Milestone Plan1.pdf", "CCC Milestone Plan 2.pdf", etc)and must not exceed 5 pages.
The plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial (UG3 and UH3 phases) to ensure its success; the processes that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met (this can be provided as a table or a graph).
All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The milestone plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. UH3 milestones should address overall recruitment and retention goals. The Terms and Conditions for a UG3 award under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NCCIH. CCC milestones of particular interest during the UG3 phase that should be described in the application may include but are not limited to:
Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/DSMB Final Informed consent(s) and, if applicable, assent forms
Agreements in place for product supply
Comprehensive laboratory plan
Pharmacy/Laboratories Identification (as applicable)
Contracts/Third Party Agreements (if applicable)
Training plan for clinical sites
Final Management/Communication Plan
Final Data and Safety Monitoring Plan
Final Study Accrual and Retention Plan
Site Performance Plan
Data Completeness and Quality Monitoring Reporting Plan
Completion of regulatory approvals
sIRB approval for clinical sites (if less than 100%, the percent of sites will be negotiated prior to UG3 award) Submission of UH3 transition request 2 months prior to the requested transition date
The application should also include a series of milestones for the completion of the specific aims of the clinical trial (UH3) phase and contingency plans. Milestones for the UH3 phase may need to be revised and finalized at the time of the UG3/ UH3 transition. Investigators and NCCIH will review and mutually agree upon a final revised UH3 milestone plan that will be included in the Terms and Conditions of the UH3 grant (if awarded). CCC milestones of particular interest during the UH3 phase that should be included in the application include but are not limited to:
Target dates for enrollment of 10%, 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
Assessment of site(s) protocol implementation performance
Collection of data related to primary and secondary endpoints and database lock
Submission of primary manuscript to peer-reviewed scientific Journal
Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date
Data sharing plan for study data and biospecimens (if applicable)
During the award phase, achievement of each milestone for the UG3 and UH3 phases will need to be communicated to the NCCIH Program Officer listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment, as defined in the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP), falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and the NCCIH, are not met, the Center may consider ending support and negotiating an orderly phase-out of the award. The NCCIH retains, as an option, periodic external peer review of progress. NCCIH staff will closely monitor progress at all trial stages including milestones, accrual, and safety.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission. Each application of a collaborative set must be on-time. Considerations for late applications that are based on the institution or PD/PI apply only to his/her individual application.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
For trials using an FDA regulated product and requiring an IND application, the applicant must either hold or be able to reference an open IND for the trial, or the applicant must obtain an IND with no clinical-hold from the FDA prior to any award. The details of the IND status of the natural product should be provided in the attachment included in the study record for section 4.6. If the FDA has granted a waiver for the trial proposed in the application, then the applicant can provide this letter as part of the response to item 4.6 in the study record. If the protocol is conducted under a non-US regulatory agency, then equivalent determinations and documentation must be provided to NCCIH prior to a grant award. Funding will not be made until the necessary regulatory approvals are in place for the conduct of the proposed clinical trial. If the product to be studied is on the Drug Enforcement Agency (DEA) controlled substance list, the applicant must describe the DEA license and registrations necessary to complete the proposed trials in the UG3 and UH3 phases. Again, no awards will be made until all necessary DEA licenses and registrations are in place.
Specific to this FOA:
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed. Each application of a collaborative set must be complete and compliant.
In order to expedite review, applicants are requested to notify the NCCIH Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Requests of $500,000 or more for direct costs in any year
Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.
The combined budgets of the CCC and DCC will be used to determine whether the policy regarding direct costs of $500,000 or more in any year will be applied (https://nccih.nih.gov/grants/policies/over500k-clinical-trials).
This policy applies when the combined budget for the collaborative DCC and CCC applications exceeds $500,000 in direct costs in any given year.
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.
In addition to the NIH policy allowed post-submission materials in NOT-OD-19-083, the follow post-submission materials are allowed:
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Specific to this FOA:
If the primary outcomes of the trial are achieved, how critical will the information be to addressing the evidence gap and advancing knowledge of theory and practice? Could results of the trial have a significant influence on clinical care and improve health? Is there sufficient demonstration for the presence of equipoise? Is there a sufficient and consistent body of relevant preclinical or clinical research of high scientific rigor to support the study rationale?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
Specific to this FOA:
How well defined are their roles and responsibilities? Have the investigatorsprovided sufficientevidence to ensure that the clinical centers will employ the appropriate personnel to recruit subjects and implement the clinical protocol? How strong is the plan for leadership and coordination of roles/responsibilities for CCC leadership? How well does the application provide evidence of necessary experience and expertise of the investigators with the natural product, the study population, and the research methods to be employed? How strong is the evidence to ensure that the clinical centers will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of publishing the results of clinical trials previously completed? How strong is the evidence is provided to demonstrate that the investigative team has successfully conducted clinical trials under an Investigational New Drug (IND) application or DEA regulations (if applicable)?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Specific to this FOA:
For Phase III clinical trials, has the investigator sufficiently described how the proposed clinical trial will change clinical practice or practice guidelines? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Does the application adequately address the following, if applicable
Study Design
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
Specific to this FOA:
What strengths and weaknesses are there in the study design? How appropriately is the study designed to answer the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? How efficient is the trial design? How strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented at all of the sites? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? Is the natural product appropriately characterized? How well are the clinical outcome measures, biological signature, dose/duration of study and follow up, appropriateness of inclusion/exclusion criteria, and sample size justified and explained? Does the application provide sufficient evidence to justify that the study population has been appropriately defined? How well does the Recruitment and Retention plan provide evidence that the accrual goals can be reached? Are adverse events appropriately captured and monitored? How effectively does the Project Management Plan identify and describe risks to implementation and how well are contingency plans described? How clear is the communication plan between DCC and CCC leadership and is it appropriate for implementing and conducting the trial? What is the quality of the DSM Plan to monitor sites/centers, and participating facilities (labs, pharmacies)? How well have the investigators described how they will follow Good Clinical Practices, Good Laboratory Practices, and Good Manufacturing Practices as appropriate?
Because this is a multi-center application, is there evidence of the ability of the individual centers to: (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure? If the clinical trial is Phase III, does the application include all relevant data to assess whether or not the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Specific to this FOA:
How strong are the facilities and resources and does the investigator sufficiently justify they are available to adequately coordinate multi-sites clinical trials? Is there strong evidence that the institutions have the available resources needed to conduct a multi-site trial at the CCC and the performance sites? How well does the application document the availability of the requisite eligible subject pool in proposed clinical site(s)? Is there sufficient documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel and facilities?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
Milestones
How strongly do the milestones address the specific aims of each phase? Are the listed milestones appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and timebound? Does the application provide reasonable and appropriate contingency plans in the event the UG3 and/or UH3 milestones are not achieved?
Data and Safety Monitoring
Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial?
For research that involves human subjects but does not involve one of thecategories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Not Applicable
For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Not Applicable.
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCCIH in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety
Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
Data Management and Sharing
Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.
Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings.Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)
Finding Help Online:http://grants.nih.gov/support/(preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:[email protected](preferred method of contact)
Telephone: 301-637-3015
Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:[email protected]
Wendy Weber, ND. Ph.D, MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov
Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov
Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.